Comparative analysis of the functionalities of the ADR reporting systems in Bulgaria and other countries in Europe

The aim of the current study is to compare the system of ADRs reporting in Bulgaria, in the context of good European practices.Material and methods: In order to perform an analysis of the European systems for ADRs reporting, two types of documentary sources of information were used. The content was analyzed in comparative terms:- Scientific publications in refereed scientific medical journals;- Websites of national centers for pharmacovigilance.Information about ADR reporting forms by patients and medical professionals was extracted from the studied sources. The organization of the systems was also studied, including the engagement of additional structures and institutions.Results and conclusions: The pharmacovigilance system in Bulgaria functions in accordance with European legislation, and despite the common principles of work of individual EU member states, there are different approaches in the organization at the national level.At least 3 different channels are available for patients and healthcare professionals to report ADRs in all analyzed countries. Online forms for reporting ADRs are readily available on the Internet. Despite the existence of different forms for patients and for health professionals, the basic volume of patient information is guaranteed through both forms.An important aspect of the activities of the agencies is the promotion of the importance of reporting ADR through various organized information campaigns

Dynamics And Sourses Of Adverse Drug Reaction Reports Related To COVID-19 Vaccines In Bulgaria

Objective: To track and analyze the dynamics of adverse drug reaction reports of authorized COVID-19 vaccines in the database of the national competent authority in Bulgaria – Bulgarian Drug Agency (BDA) and to identify the sources of ADR in our country during the considered time period.Material and methods: For the analysis of ADR reports, the specialized database of the national competent authority in Bulgaria was used, containing information on all reported adverse drug reactions for the period 01.01.2018 - 31.03.2022.Results and conclusions: The first report of an ADR with a suspected connection to a vaccine against COVID-19 (with the trade name Comirnaty) was received in the BDA on 27.12.2020, on the first day of the start of the vaccination process in Bulgaria and the EU.The number of ADRs reported after SARS-CoV-2 immunization in the period of the study was about 2.3 times greater than the number of ADRs reported after taking any other drugs. Patients showed a higher activity in reporting ADRs for the studied period (90% of all reports were submitted by patients), which is significantly higher than previous periods. The increase in the number of ADR reports is not smooth, but 3 peaks are emerging: in the months of February, July and November of 2021

Potential Drug-Drug Interactions With Tyrosine Kinase Inhibitors

През последните години се наблюдава голям напредък при лечението на туморните заболявания поради въвеждането на нови фармакологични подходи като таргетната терапия и имунотерапията. Таргетната терапия се състои в потискане активността на специфични таргетни молекули в туморните клетки, необходими за клетъчния им растеж, диференциация и оцеляване. Особен интерес представляват инхибиторите на тирозин киназите, протеини, които играят основна роля в клетъчната сигнализация, тъй като свръхекспресия или мутантни форми на голям брой тирозин кинази са открити при множество тумори. Тирозин киназните инхибитори блокират активността на тирозин киназите и нарушават вътреклетъчната сигнална трансдукция, като по този начин потискат растежа и развитието на раковите клетки. Лечението с тирозин киназни инхибитори се понася добре, като един от основните проблеми при приложението им е повишеният риск от възникване на лекарствени взаимодействия при едновременен прием с други лекарства.В настоящия обзор са описани потенциалните лекарствени взаимодействия, които биха могли да възникнат при лечение с някои тирозин киназни инхибитори (ALK инхибитори, TRK инхибитори, EGFR инхибитори, FGFR инхибитори), използвани за лечение на редки и агресивни форми на рак. Необходимо е внимателно подбиране на лекарствата, които се приемат едновременно с тирозин киназните инхибитори с цел да се избегнат промени в плазмените им концентрации, които могат да рефлектират върху терапевтичните и токсичните им ефекти.There has been great progress in the treatment of tumors in recent years due to the introduction of new pharmacological approaches such as targeted therapy and immunotherapy. Targeted therapy is associated with suppressing the activity of specific targeting molecules in the cancer cells necessary for their growth, differentiation and survival. Of particular interest are tyrosine kinase inhibitors, proteins that play a major role in cell signaling, since overexpression or mutant forms of a large number of tyrosine kinases have been found in multiple tumors. Tyrosine kinase inhibitors block the activity of tyrosine kinases and disrupt intracellular signal transduction, thereby inhibiting the growth and development of cancer cells. Treatment with tyrosine kinase inhibitors is well tolerated and one of the main problems with their administration is the increased risk of drug interactions when co-administered with other drugs.This review describes the potential drug-drug interactions that may occur during the treatment with certain tyrosine kinase inhibitors (ALK inhibitors, TRK inhibitors, EGFR inhibitors, FGFR inhibitors) used to treat rare and aggressive tumors. Careful selection of drugs that are co-administered with tyrosine kinase inhibitors is needed in order to avoid changes in their plasma concentrations that may lead to changes in their therapeutic and toxic effects

Monitoring the Safety of Vaccines Against Covid-19 – Analysis of the Adverse Drug Reaction Reports in Bulgaria // Проследяване безопасността на ваксини срещу Covid-19 – анализ на съобщенията за нежелани лекарствени реакции в България

The emergence of the coronavirus disease (COVID-19) at the end of 2019, caused by the SARS-CoV-2 virus, its rapid and global spread, the assessment of the risks to societies led to the declaration of a pandemic situation by the World Health Organization on March 11, 2020. The international scientific community has mobilised efforts to research and develop vaccines against SARS-CoV-2. The dissertation aims to analyse the system for reporting ADRs in Bulgaria in the context of good European practices and the dynamics and specificity of reports of adverse drug reactions after administering vaccines against COVID-19 to optimise the processes for medicines safety monitoring. The research methodology includes ADR Analysis, documentary method and statistical method. To perform the research tasks related to the analysis of ADR reports, the specialised database of BDA was used, and the contained information on all reported adverse drug reactions (ADRs) for the period 01.01.2018 - 31.03.2022, as well as on the unified information system for vaccines administered in the country. The number of ADRs reported after SARS-CoV-2 immunisation in the study period was about 2.3 times greater than those reported after taking other drugs. The reactogenicity of vaccines, determined by the number of reported reports and the number of ADRs (in parentheses) per 100,000 doses, is as follows: Comirnaty 77 (142), Spikevax 163 (354), Jcovden 66 (132), Vaxzevria: 977 (1899). Therefore, the reactogenicity of Vaxzevria is 12.7 times greater than Comirnaty, according to the number of reports and 13.4 times more significant, according to the number of ADRs. The number of ADRs reported per 100,000 doses in women was about 2 times higher than in men, consistent with the results of many other safety studies. The highest reporting of ADRs for all four types of vaccines is in the age group of 25-49 years, followed by 18-24 years and 12-15 years. Serious ADRs with the Comirnaty and Vaxzevria vaccines occurred at a higher mean age in both sexes. With Spikevax, serious ADRs occurred among women at a higher mean age, and in men, serious ADRs tended to occur at a lower mean age. For the Jcovden vaccine, trends were similar to Spikevax but lacked significance. Higher activity in reporting ADRs for the studied period is shown by patients (patients submit 90% of all reports), which is significantly higher than the average level for European countries, where medical specialists are more active. There is potential to optimise the system for monitoring drug safety by more actively involving and stimulating medical specialists in the process and ensuring strategic investments in deploying the structural and resource potential of the system. Despite the common principles of operation of the individual EU member states, there are different approaches to the organisation of the MDS systems. The systems analysis shows that in some countries (e.g. the Netherlands), MDS activities are carried out by an independent institution engaged in the collection and analysis of ADR data and feedback to all stakeholders.Появата на коронавирусната болест (COVID-19) в края на 2019 година, причинена от вируса SARS-CoV-2, бързото и глобалното ѝ разпространение, оценката на рисковете за обществата доведе до обявяване на ситуация на пандемия от Световната здравна организация нa 11 март 2020 година. Международната научна общност мобилизира усилия за проучването и разработването на ваксини срещу SARS-CoV-2. Целта на дисертационен труд е да се анализира системата за съобщаване на НЛР в България, в контекста на добрите европейски практики, както и динамиката и спецификата на подаваните съобщения за нежелани лекарствени реакции след поставяне на ваксини срещу COVID-19, с оглед оптимизиране на процесите за проследяване на лекарствена безопасност. Методиката на проучването включва Анализ на НЛР, документален метод и статистически метод. За изпълнение на задачите на проучването, свързани с анализа на съобщенията за НЛР, е използвана специализираната база данни на ИАЛ и съдържащата се информация за всички съобщени нежелани лекарствени реакции (НЛР) за периода 01.01.2018 – 31.03.2022 г., както и на единната информационна система за поставяните в страната ваксини. Информацията и данните за НЛР, свързани конкретно с приложението на ваксини срещу COVID-19, анализирани и представени в настоящото проучване, са получени в периода 27.12.2020-31.03.2022. Броят на съобщенията за НЛР, получени след имунизация срещу SARS-CoV-2 в изследвания период, е около 2.3 пъти по-голям от броя на съобщенията за НЛР, получени след прием на други лекарства. Реактогенността на ваксините, определена чрез броя на подадени съобщения и броя на НЛР (отразена в скоби) на 100000 дози, e следната: Comirnaty 77 (142), Spikevax 163 (354), Jcovden 66 (132), Vaxzevria: 977 (1899). Следователно реактогенността на Vaxzevria e 12.7 пъти по-голяма от тази на Comirnaty според броя на съобщенията и 13.4 пъти по-голяма според броя на НЛР. Броят на съобщенията за НЛР на 100000 дози при жените е около 2 пъти по-голям от този при мъжете, в съответствие с резултатите от много други проучвания за безопасност. Най-висока съобщаемост на НЛР и при четирите вида ваксини има във възрастта 25-49 г., следвана от 18-24 г. и 12-15 години. Сериозните НЛР при ваксините Comirnaty и Vaxzevria възникват при по-висока средна възраст и при двата пола. При Spikevax сред жените сериозните НЛР са на по-висока средна възраст, а при мъжете има тенденция сериозните НЛР да се проявяват на по-ниска средна възраст. При ваксината Jcovden тенденциите са като при Spikevax, но липсва значимост. По-висока активност в съобщаването на НЛР за изследвания период показват пациентите (90% от всички съобщения са подадени от пациенти), която е значително по-висока от средното ниво за европейските страни, където по-активни са медицинските специалисти. Съществува потенциал за оптимизиране на системата за проследяване на лекарствената безопасност чрез по-активно въвличане и стимулиране на медицинските специалисти в процеса и осигуряване на стратегически инвестиции в разгръщане на структурния и ресурсен потенциал на системата. Въпреки общите принципи на работа на отделните държави членки в ЕС, съществуват различни подходи в организацията на системите за ПЛБ. Извършеният анализ на системите показва, че в някои страни (напр. Нидерландия) дейностите по ПЛБ се извършват от независима институция, ангажирана не само със събиране, но и с анализ на данни за НЛР и обратна връзка към всички заинтересовани страни

The pharmacological basis for application of cannabidiol in cancer chemotherapy

Chemotherapy is one of the therapeutic approaches for cancer treatment and has demonstrated great success with the introduction of selectively acting molecules against specific biomarkers of some types of tumors. Despite this success there is a large unmet need for novel therapies that provide effective control on the progression of advanced or drug-resistant cancer diseases. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, as possible agents for cancer therapy. We analyzed the anticancer properties and mechanism of action of cannabidiol (CBD), the main non-psychoactive cannabinoid received from hemp of Cannabis plant. Despite of data for pleiotropic effects of CBD, we here present the results for the efficacy of CBD in the modulation of different stages of cancer development. The analysis of the anticancer properties of CBD is made in relation to the proposed or newly discovered molecular targets of action. Thereafter, we consider the specific effects of CBD on primary tumors, their invasiveness and metastases, whether the influence on identified tumor markers in different types of tumors reflect the therapeutic potential of CBD. The studies reviewed herein indicate that CBD elicit activity through the cannabinoid receptor dependent and independent pathways. The processes such as ceramide production, ER-stress, autophagy and apoptosis, angiogenesis and matrix remodeling also appear to regulate the anticancer activity of CBD. So, the pharmacological basis for therapeutic application of CBD is constructed on the scientific data for its antitumor activity, extensively provided studies in vitro and in vivo in animal tumor models, and available data on the safety profile of clinically approved CBD products. We also try to reduce the deficits of our understanding in relation of pharmacological synergistic interactions of CBD with cytostatic drugs, where data remains limited. It is recognized that more studies for defining the specific molecular and signaling mechanisms of anticancer action of cannabinoids, particularly CBD, requires further evaluation. We believe that the therapeutic advantages of CBD are associated not only with its non-psychoactive behavior, but also are related to its influence on the important biochemical pathways and signal molecules, defining the genome instability and specific changes of the malignant tumor cells

Analysis of good distribution practice inspection deficiency data of pharmaceutical wholesalers in Bulgaria

The current study analyses the regulatory inspection findings of the wholesalers in Bulgaria in 2017 and compares the results with the findings from some other EU member-states. In total, 48 GDP inspections were performed in 2017. 50% of the inspections were performed in relation with issuing an authorization for wholesale of medicines, the rest half were related to changes in already granted authorizations. During the inspections, 17 non-conformities (NCs) have been documented. The NCs were identified in 3 wholesalers and 6 deficiencies were classified as major. No critical deficiencies were found. NCs were found in 6.25% of the inspected companies. No critical NCs were identified and only 6 NCs were classified as major which demonstrated high level of compliance of distributions sites in Bulgaria with the requirements of GDP

Good Manufacturing Practice for Medicinal Products in Bulgaria: an Analysis of Regulatory Inspection Findings

Background: The manufacture of medicinal products for human use in the European Economic Area is governed by European Directives and Regulations stipulating the relevant principles and guidelines of Good Manufacturing Practice, describing the minimum standard to be fulfilled in the production processes. Aim: To present analysis of the deficiencies reported following Good Manufacturing Practice inspections in Bulgaria in two consecutive years (2016, 2017) and to compare them with results from similar inspections reported by other EU member states. Materials and methods: A retrospective study was carried out by reviewing the complete Good Manufacturing Practice inspection reports of all manufacturers conducted by the Bulgarian Drug Agency in 2016 and 2017, according to relevant requirements and applicable local legislation. The items reviewed were scope of inspection, type of companies, classification of deficiencies – ‘critical’, ‘major’ and ‘other significant deficiencies’, their nature and reference to EU Good Manufacturing Practice. Results: The analyzed data included 55 inspections, revealing 460 various deficiencies, of which 2 were critical and 102 – major. Twenty inspections were performed in 2016 vs. 35 inspections in 2017.The pattern of deficiencies was similar to the findings of other EU regulatory agencies, showing that equivalent requirements were applied. Our analysis showed that Bulgarian Drug Agency inspectors rarely raised deficiencies related to Computer Systems, Qualification/Validation, Personnel and Qualification of Suppliers unlike other EU regulators agents. Conclusions: Our analysis of Good Manufacturing Practice inspection findings in 2016 and 2017 showed that the Bulgarian Drug Agency demonstrated its ability to detect non-compliances and take necessary regulatory actions. Quality related issues constitute the main reasons for non-compliances with the requirements.Publishing the results from the inspections performed by the national competent authorities enhances the regulatory transparency that can be useful for industry to improve its Good Manufacturing Practice compliance

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia